bims-ecemfi Biomed News
on ECM and fibroblasts
Issue of 2025–05–11
twelve papers selected by
Badri Narayanan Narasimhan, University of California, San Diego
  1. Effects of PDMS Culture on Stem Cell Differentiation Towards Definitive Endoderm and Hepatocytes.
  2. Self-propagating wave drives morphogenesis of skull bones in vivo.
  3. Confined Migration Drives Stem Cell Differentiation.
  4. F-actin Dynamics Regulates Collective Cell Migration by Modulating Cell Shape and Stress Correlation.
  5. RGD peptide hydrogel downregulates mechanosignal YAP to inhibit postoperative scarring.
  6. Cadherin Dynamics and Cortical Tension in Remodeling Cell-Cell Adhesion During EMT.
  7. Persistent pseudopod splitting is an effective chemotaxis strategy in shallow gradients.
  8. Biomimetic Hydrogels from Mixed Gellan Gum and Tryptophan Zipper Self-Assembling Peptides.
  9. Polymer oxidation: A strategy for the controlled degradation of injectable cryogels.
  10. Invasive phenotypes of triple-negative breast cancer-associated fibroblasts are mechanosensitive, AhR-dependent and correlate with disease state.
  11. Strong and Fatigue-Resistant Hydrogels via Poor Solvent Evaporation Assisted Hot-Stretching for Tendon Repair.
  12. Restructuring of Hydrogel Polymer Networks via Ion Storming.
  1. Acta Biomater. 2025 May 07. pii: S1742-7061(25)00342-3. [Epub ahead of print]
    Effects of PDMS Culture on Stem Cell Differentiation Towards Definitive Endoderm and Hepatocytes.
    Christopher T Clark, Yao Wang, Devin C Johnson, Seohyun C Lee, Quinton Smith.
      The generation of human induced pluripotent stem cell (hiPSC) derivatives for regenerative medicine applications holds tremendous promise in treating various disorders. One critical target includes liver disease, in which the primary curative treatment is a cellular transplant aimed to restore the loss function of hepatocytes. In an effort to improve the differentiation of hiPSC-derived liver tissue, we manipulated the mechanical conditions of endoderm specification through directed perturbation of the cytoskeleton and through 2D substrate culture on viscoelastic materials. Through a combination of qRT-PCR, immunofluorescence staining, and functional assays, we found that mechanical cues can bias endoderm specification in an actomyosin and Yes-associated protein (YAP) dependent manner, unveiling new insights into mechanotransduction in germ layer specification and downstream maturation toward parenchymal cells. STATEMENT OF SIGNIFICANCE: The translational potential of using human induced pluripotent stem cell (hiPSC) derived hepatocytes, to therapeutically improve impaired liver function holds great clinical promise. However, challenges remain in efficiently differentiating functional hepatocytes with mature marker expression. In an effort to improve the differentiation efficiency of hepatocytes, the role of early mechanosensing mechanisms was investigated in the specification of hiPSCs to definitive endoderm progenitor populations. Through a combination of cytoskeletal modulation, control of mechanoresponsive, yes-associated protein expression, and culture on physiologically compliant PDMS substrates, we found that soft environments not only improve progenitor specification but also impact the downstream functionality of differentiated hepatocytes. These results contribute to the collective appreciation that mechanical cues are critical in developmental processes.
    Keywords:  PDMS; Substrate stiffness; induced pluripotent stem cells; liver tissue engineering; mechanosensing
    DOI:  https://doi.org/10.1016/j.actbio.2025.05.017
  2. Nat Commun. 2025 May 09. 16(1): 4330
    Self-propagating wave drives morphogenesis of skull bones in vivo.
    Yiteng Dang, Johanna Lattner, Adrian A Lahola-Chomiak, Diana Alves Afonso, Elke Ulbricht, Anna Taubenberger, Steffen Rulands, Jacqueline M Tabler.
      Cellular motion is a key feature of tissue morphogenesis and is often driven by migration. However, migration need not explain cell motion in contexts where there is little free space or no obvious substrate, such as those found during organogenesis of mesenchymal organs including the embryonic skull. Through ex vivo imaging, biophysical modeling, and perturbation experiments, we find that mechanical feedback between cell fate and stiffness drives bone expansion and controls bone size in vivo. This mechanical feedback system is sufficient to propagate a wave of differentiation that establishes a collagen gradient which we find sufficient to describe patterns of osteoblast motion. Our work provides a mechanism for coordinated motion that may not rely upon cell migration but on emergent properties of the mesenchymal collective. Identification of such alternative mechanisms of mechanochemical coupling between differentiation and morphogenesis will help in understanding how directed cellular motility arises in complex environments with inhomogeneous material properties.
    DOI:  https://doi.org/10.1038/s41467-025-59164-9
  3. Adv Sci (Weinh). 2025 May 08. e2415407
    Confined Migration Drives Stem Cell Differentiation.
    Xu Gao, Yixuan Li, Jia Wen Nicole Lee, Jianxuan Zhou, Vaishnavi Rangaraj, Jennifer Marlena, Andrew W Holle.
      In both endogenous and exogenously-introduced human mesenchymal stem cells (hMSCs), homing to sites of regeneration requires navigation through complex extracellular matrix environments that impose confinement on migrating cells. Despite its prevalence in vivo, the impact of confinement on hMSC differentiation remains poorly understood. To address these questions, a physiologically relevant, flow-free polydimethylsiloxane-based microchannel system with confining widths ranging from 3 to 10 µm in width, is developed. In these microchannel systems, it is found that hMSCs migrate faster and experience significant nuclear deformation in 3 µm wide channels compared to wider 10 µm channels. These morphological changes persist for days postexit, implying that stem cells possess a mechanical memory of their past confined migration. High degrees of nuclear deformation also correlated with substantial changes in genome regulation, as cells displayed significant H3K9 acetylation postconfinement. In these postconfinement stem cells, significantly higher expression levels of RUNX2 along with a higher degree of nuclear-to-cytoplasmic shuttling are found, suggesting that short confined migration can stimulate osteogenic differentiation. Finally, it is found that nuclear mechanosensing via the cytoskeleton is not the primary factor driving confinement-induced differentiation. These results suggest that physiological confinement can serve as a key mechanical cue promoting early osteogenic differentiation in hMSCs.
    Keywords:  confined migration; human mesenchymal stem cells; nuclear mechanosensing; stem cell differentiation; stem cell epigenetics
    DOI:  https://doi.org/10.1002/advs.202415407
  4. Biophys J. 2025 May 02. pii: S0006-3495(25)00276-0. [Epub ahead of print]
    F-actin Dynamics Regulates Collective Cell Migration by Modulating Cell Shape and Stress Correlation.
    Xiangdong Kong, Zheng Zhong, Chao Fang.
      As an essential component in generating cell contractility, F-actin plays a pivotal role in collective cell migration. However, the mechanisms by which subcellular F-actin dynamics influence the collective behaviors of cell clusters across scales remain poorly understood. In this study, we developed a mechanical model to investigate how the dynamics of stress fibers and cryptic lamellipodia, prominent F-actin structures generating traction forces, regulate collective cell migration. Our results show that strengthening stress fibers significantly amplifies cell rearrangements and counteracts the high-density induced inhibition of cell movements in the monolayer. It is attributed to the tension-caused cell elongation, which facilitates the growth of normalized mean squared displacements (NMSD) in high-density cell monolayers. Moreover, the model shows that stronger stress fibers could effectively guide collaborative cell movements through enhancing the spatial correlation of maximum principal stress. Additionally, we found cryptic lamellipodia exhibit similar influence on collective cell migration. Our results bridge intracellular F-actin dynamics with collective cell migration, offering insights into the underlying mechanisms and their biological significance.
    DOI:  https://doi.org/10.1016/j.bpj.2025.04.030
  5. Acta Biomater. 2025 May 01. pii: S1742-7061(25)00313-7. [Epub ahead of print]
    RGD peptide hydrogel downregulates mechanosignal YAP to inhibit postoperative scarring.
    Yao Lv, Licheng Liang, Mian Qin, Ru-Ping Jiang, Fei-Fei Zong, Xia Wu, Kai-Li Wu, Liang Liang.
       OBJECTIVE: Glaucoma filtration failure may result from an overabundance of human Tenon's capsule fibroblasts (HTFs) forming a filtration tract scar. Conversely, the Yes-associated protein (YAP), a transcriptional activator of the Hippo signaling pathway, is a crucial matrix stiffness regulator of matrix production and fibroblast activation. With superior biocompatibility and biodegradability, RGD peptide hydrogels imitate the structure of real tissues' extracellular matrix (ECM). The purpose of this research was to determine whether down-regulating YAP expression via RGD peptide hydrogels may prevent HTFs activation and ECM protein secretion. Transforming growth factor-β2 (TGF-β2) was used to induce the activation of HTFs in a cellular model of scarring following glaucoma filtration surgery. Utilizing SD rats, a murine model of subconjunctival injury was established. The shape of collagen fibers was observed through Masson staining, and the expression of YAP and α-smooth muscle actin (α-SMA) was identified through immunohistochemistry. RGD peptide hydrogel was discovered to have anti-scarring properties in a mouse eye injury model, as well as the ability to lessen HTFs activation, YAP expression, cytosolic nucleus accumulation, and the expression of connective tissue growth factor (CTGF) and ECM proteins. The best concentration was found to be 1.0 weight percent among them. This concentration not only makes it easier to inject a drug subconjunctivally in vivo and maintain the filtration vesicle space in the conjunctiva, but it also inhibits the activation of fibroblasts into myofibroblasts and down-regulates the expression of the Hippo-YAP signaling pathway in Tenon's capsule fibroblasts.
    STATEMENT OF SIGNIFICANCE: 1. The homogenous reticular three-dimensional nanostructure that made up the interior structure of the 1.0 weight percent gel had good drug delivery characteristics for long-lasting controlled drug release. 2. RGD peptide hydrogel had a certain matrix hardness, which could mimic the normal connective tissue hardness under the conjunctiva. 3. RGD peptide hydrogels could prevented the development of rat conjunctival fibrosis. 4. RGD peptide hydrogel could inhibit the expression of YAP and its target gene CTGF, as well as α-SMA, ECM proteins in HTFs. 5. RGD peptide hydrogel has good biocompatibility, biodegradability, and stable mechanical properties, and can also be used as a promising carrier for the controlled release of drugs.
    Keywords:  Extracellular matrix; RGD peptide hydrogel; Scarring; Tenon's capsule fibroblasts; Yes-associated protein
    DOI:  https://doi.org/10.1016/j.actbio.2025.04.059
  6. Biophys J. 2025 May 05. pii: S0006-3495(25)00280-2. [Epub ahead of print]
    Cadherin Dynamics and Cortical Tension in Remodeling Cell-Cell Adhesion During EMT.
    Hongyuan Zhu, Xiaoxi Liu, Jiayu Zhang, Guoqing Zhao, Jin Wang, Huan Zhang, Yan Liu, Hui Guo, Jin Yang, Zheng Wang, Tian Jian Lu, Feng Xu, Min Lin.
      Epithelial-to-mesenchymal transition (EMT), a key process in cancer metastasis and fibrosis, disrupts cellular adhesion by replacing epithelial E-cadherin with mesenchymal N-cadherin. While, how the shift from E-cadherin to N-cadherin impacts molecular-scale adhesion mechanics and cluster dynamics-and how these changes weaken adhesion under varying mechanical and environmental conditions-remains poorly understood, limiting our ability to target EMT-driven pathological adhesion dynamics. Here, we developed a unified Lattice-Clutch model to investigate cadherin clustering, cortical tension, and adhesion strength during EMT. Using atomic force microscopy (AFM) experiments, we measured the mechanical properties of single cadherin trans-bonds and cadherin-mediated cell-cell and cell-matrix adhesions across varying conditions. Our results demonstrate that N-cadherin trans-bonds are mechanically weaker than E-cadherin trans-bonds, leading to reduced adhesion strength during EMT. Computational modeling and experimental validation further revealed that EMT impairs cadherin clustering and cortical tension regulation, which collectively weaken both cell-cell and cell-matrix adhesions, particularly on stiff substrates. These findings highlight how EMT disrupts adhesion strength at multiple scales-from individual cadherin bonds to collective cluster dynamics. Our study elucidates how EMT-driven changes in cadherin type weaken adhesion strength and mechanotransduction, providing insights into cellular adhesion mechanics and potential therapeutic strategies for targeting EMT-associated diseases such as cancer metastasis and tissue remodeling.
    Keywords:  Cadherin Clustering; Cortical Tension; Epithelial-to-mesenchymal transition; Mechanical Model; Mechanochemical Coupling
    DOI:  https://doi.org/10.1016/j.bpj.2025.05.001
  7. Proc Natl Acad Sci U S A. 2025 May 13. 122(19): e2502368122
    Persistent pseudopod splitting is an effective chemotaxis strategy in shallow gradients.
    Albert Alonso, Julius B Kirkegaard, Robert G Endres.
      Single-cell organisms and various cell types use a range of motility modes when following a chemical gradient, but it is unclear which mode is best suited for different gradients. Here, we model directional decision-making in chemotactic amoeboid cells as a stimulus-dependent actin recruitment contest. Pseudopods extending from the cell body compete for a finite actin pool to push the cell in their direction until one pseudopod wins and determines the direction of movement. Our minimal model provides a quantitative understanding of the strategies cells use to reach the physical limit of accurate chemotaxis, aligning with data without explicit gradient sensing or cellular memory for persistence. To generalize our model, we employ reinforcement learning optimization to study the effect of pseudopod suppression, a simple but effective cellular algorithm by which cells can suppress possible directions of movement. Different pseudopod-based chemotaxis strategies emerge naturally depending on the environment and its dynamics. For instance, in static gradients, cells can react faster at the cost of pseudopod accuracy, which is particularly useful in noisy, shallow gradients where it paradoxically increases chemotactic accuracy. In contrast, in dynamics gradients, cells form de novo pseudopods. Overall, our work demonstrates mechanical intelligence for high chemotaxis performance with minimal cellular regulation.
    Keywords:  chemotaxis; mechanical intelligence; physical limits; pseudopods; reinforcement learning
    DOI:  https://doi.org/10.1073/pnas.2502368122
  8. ACS Macro Lett. 2025 May 09. 679-686
    Biomimetic Hydrogels from Mixed Gellan Gum and Tryptophan Zipper Self-Assembling Peptides.
    Riddhesh Doshi, Dhushanthan Mohanathas, Md Shariful Islam, Juanfang Ruan, Richard D Tilley, Kristopher A Kilian.
      Peptide self-assembly has been used to fabricate synthetic hydrogels that emulate many of the chemical and physical properties of natural hydrogels. However, these materials often lack stability for many applications and do not display the native bioactivity found in tissue. Here we demonstrate a hybrid hydrogel system in which self-assembling peptides are integrated with polysaccharides to enhance gelation and provide improved mechanics and bioactivity. A peptide based on the tryptophan zipper (trpzip) motif was mixed with the anionic polysaccharide gellan gum, demonstrating gelation within minutes with increased stiffness compared to that of trpzip alone. The hybrid material maintained viscoelastic character with shear-thinning, self-healing, and stress-relaxation on the order of natural materials like collagen. All hydrogels supported cell adhesion and viability with increased gellan gum content, promoting cell assembly into aggregates. The enhanced gelation kinetics, stability, self-healing, and bioactivity of these materials make them promising candidates as matrices for cell culture and reagents for biofabrication and syringe extrusion for biological delivery.
    DOI:  https://doi.org/10.1021/acsmacrolett.5c00076
  9. Mater Today Bio. 2025 Jun;32 101743
    Polymer oxidation: A strategy for the controlled degradation of injectable cryogels.
    Alexandra Nukovic, Mohammad Hamrangsekachaee, Mahalakshmi Rajkumar, Gwyneth Wong, Emily R Tressler, Sara M Hashmi, Stephen M Hatfield, Sidi A Bencherif.
      Cryogels, an advanced subclass of hydrogels, are widely used in biomedical applications such as tissue engineering, drug delivery, and immunotherapy. Biopolymers, like hyaluronic acid (HA), are key building blocks for cryogel fabrication due to their intrinsic biological properties, biocompatibility, and biodegradability. HA undergoes biodegradation through hydrolysis, enzymatic degradation, and oxidation, but becomes less susceptible to degradation once chemically modified. This modification is necessary for producing HA-based cryogels with unique properties, including an open macroporous network, mechanical resilience, shape memory, and syringe injectability. Endowing cryogels with resorbable features is essential for meeting regulatory requirements and improving treatment outcomes. To this end, HA was oxidized with sodium periodate (HAox) and chemically modified with glycidyl methacrylate (HAoxGM) to create HAoxGM cryogels with controlled degradation. Oxidation of HA increased the susceptibility of the polymer backbone to breakdown through various mechanisms, including oxidative cleavage and alkaline hydrolysis. Compared to their poorly degradable counterparts, HAoxGM cryogels retained their advantageous properties despite reduced compressive strength. HAoxGM cryogels were highly cytocompatible, biocompatible, and tunable in degradation. When injected subcutaneously into mice, the HAoxGM cryogels were biocompatible and resorbed within two weeks. To validate the beneficial effect of controlled biodegradation in a relevant in vivo setting, we demonstrated that the degradation of HAoxGM cryogels accelerates ovalbumin release and enhances its uptake and response by immune cells in mice. This versatile oxidation strategy can be applied to a wide range of polymers, allowing better control over cryogel degradation, and advancing their potential for biomedical applications and clinical translation.
    Keywords:  Biocompatibility; Cryogel; Degradation; Hydrolysis; Oxidation
    DOI:  https://doi.org/10.1016/j.mtbio.2025.101743
  10. Acta Biomater. 2025 May 01. pii: S1742-7061(25)00314-9. [Epub ahead of print]
    Invasive phenotypes of triple-negative breast cancer-associated fibroblasts are mechanosensitive, AhR-dependent and correlate with disease state.
    Gabrielle Brewer, Paul Savage, Anne-Marie Fortier, Hong Zhao, Alain Pacis, Yu-Chang Wang, Dongmei Zuo, Monyse de Nobrega, Annika Pedersen, Camille Cassel de Camps, Margarita Souleimanova, Valentina Muñoz Ramos, Jiannis Ragoussis, Morag Park, Christopher Moraes.
      Cancer associated fibroblasts (CAFs) play a critically important role in facilitating tumour cell invasion during metastasis. They also modulate local biophysical features of the tumour microenvironment through the formation of fibrotic foci, which have been correlated with breast cancer aggression. However, the impact of the evolving three-dimensional biophysical tumour microenvironment on CAF function remains undefined. Here, by isolating CAFs from primary human triple-negative breast cancer tissue at the time of surgery, we find that their ability to remodel the local microenvironment and invade into a three-dimensional matrix correlates with disease state. We then engineered culture models to systematically deconstruct and recreate mechanical tissue features of early breast cancer fibrotic foci; and demonstrate that invasion is mechanically-activated only in CAFs from patients with no detectable pre-existing metastases, but is independent of mechanical cues in CAFs isolated from patients with later-stage axillary lymph node metastases. By comparing the differential transcriptional response of these cells to microenvironmental tissue stiffness, we identify the aryl hydrocarbon receptor (AhR) as being significantly upregulated in invasive sub-populations of both mechanically-activated and mechanically-insensitive CAFs. Increasing AhR expression in CAFs induced invasion, while suppressing AhR significantly reduced invasion in both mechanically-activated and mechanically-insensitive CAF populations, even on stiffnesses that recapitulate late-stage disease. This work therefore uses mechanobiological analyses to identify AhR as a mediator of CAF invasion, providing a potential stratification marker to identify those patients who might respond to future mechanics-based prophylactic therapies, and provides a targetable mechanism to limit CAF-associated metastatic disease progression in triple-negative breast cancer patients. STATEMENT OF SIGNIFICANCE: By designing a mechanically-tunable tissue-engineered model of fibroblastic foci, and using this to culture patient-derived cancer-associated fibroblasts, we demonstrate that these cells are differentially mechanosensitive, depending on disease stage of the patient. While comparing transcriptomic profiles of patient-derived cells produces too many pathways to screen, identifying the pathways activated by local tissue mechanics that were common across each patient allowed us to identify a specific target to limit fibroblast invasion. This broad discovery strategy may be useful across a variety of biomaterials-based tissue engineered models; and these specific findings suggest (1) a strategy to identify patients who might respond to CAF- or matrix-targeting therapies, and (2) a specific actionable target to limit CAF-associated metastatic disease progression.
    Keywords:  Aryl hydrocarbon receptor; Cancer-associated fibroblasts; Contraction; Fibrotic foci; Invasion; Mechanobiology; Remodelling; Stiffness; Triple-negative breast cancer
    DOI:  https://doi.org/10.1016/j.actbio.2025.04.061
  11. Adv Sci (Weinh). 2025 May 08. e2503697
    Strong and Fatigue-Resistant Hydrogels via Poor Solvent Evaporation Assisted Hot-Stretching for Tendon Repair.
    Huamin Li, Ying Zhang, Haidi Wu, Zhanqi Liu, Cheng Guan, Jin Zhang, Jingyi Chen, Shaohua He, Xuewu Huang, Wancheng Gu, Yiu Wing Mai, Jiefeng Gao.
      It is highly desirable but still remains challenging to develop high-performance hydrogels with satisfactory mechanical properties for tissue engineering. Here, anisotropic yet transparent hydrogels (AHs) are prepared for tendon repair via a facile "poor solvent evaporation assisted hot-stretching" strategy. AHs have great mechanical properties with tensile strength, toughness, and fracture energy as high as 33.14 ± 2.05 MPa, 44.1 ± 3.5 MJ m-3, and 106.18 ± 7.2 kJ m-2, respectively. Especially, AHs show unique flaw-insensitive characteristics, and cracks can only deflect along the fiber alignment direction rather than propagate transverse to this direction, showing an interesting self-protection function. The high strength, toughness, and fatigue resistance originate from the hierarchal structure of AHs, i.e., the densified polymeric network comprising fiber bundles and nanofibrils with aligned macromolecular chains, crystalline domains, and intermolecular hydrogen bonds. AHs with superior biocompatibility and swelling resistance can be used to repair rat tendons, and implantation of AHs can promote collagen regeneration for the tendon repair. This study provides a new method to fabricate strong and anti-fatigue hydrogels as a new class of promising materials for soft tissues.
    Keywords:  anisotropic hydrogels; flaw‐insensitivity; hot‐stretching; poor solvent evaporation; tendon repair
    DOI:  https://doi.org/10.1002/advs.202503697
  12. Small. 2025 May 07. e2502436
    Restructuring of Hydrogel Polymer Networks via Ion Storming.
    Weicheng Kong, Yuling Lu, Ximin Yuan, Yong He.
      Hydrogel is a 3D network gel with high hydrophilicity, and its mechanical properties are weakened by the disordered polymer network. Although traditional techniques such as directional freezing and salting-out improve the mechanical properties of the hydrogel, the biomedical and chemical engineering applications are limited by the complex processing procedures. In view of this situation, an urgent demand for the non-intrusive in situ hydrogel processing technique is required, and the disordered polymer network resembles a tangled yarn that can be unraveled through the external electric field. It is of interest to elucidate whether there are countless ions at the atomic-scale that can instantly align the disordered polymer networks in the hydrogel. In this study, it is first demonstrated that these ions can move in the hydrogels under the action of the electric field. The rapid ion vibrations break the hydrogen bonds to restructure the networks under the action of the high-frequency electric field, and the soft hydrogel is formed; while that generates the coordination under the action of the low-frequency field, and the tough hydrogel is obtained. This technique integrates the structure and material in the hydrogels, which enhances the mechanical properties of the 3D-printed hydrogel components.
    Keywords:  coordination; electric training; hydrogel; ion storm; mechanical property; training solution
    DOI:  https://doi.org/10.1002/smll.202502436
This page is being maintained by Thomas Krichel. It was last updated on 2025‒05‒11 at 2:29.